Methods and paradigms are proposed for maintaining rats for extended periods of time (20-25% of mature life span) in order to attempt to both retard and/or accelerate rate of development of brain aging pathology using long-term hormonal-pharmacological manipulations. Animals would be maintained behind an air barrier system to prevent airborne infections. For 6-7 months, rats will be given specific hormonal and pharmacological agents for which there are some data available suggesting a possible relationship to brain aging mechanisms. The animals will be tested for learning, motivation and sensory-motor functions. The brains of animals will then be morphometrically analyzed in detail at the light and electron microscopic levels. In particular, attempts will be made to determine if the electron microscopic brain changes induced by hormonal treatments are similar in detailed pattern of sequence and topography to those seen during normal aging. Plasma assays of hormones, electrolytes, glucose, etc. are also proposed in order to attempt to analyze the underlying mechanisms of hormone effects. It seems important to attempt to both retard and to accelerate brain measures of aging by long-term hormonal manipulations in order to test hypotheses which attribute a specific aging role to endocrine mechanisms. The special value of long-term studies for experimental attempts to retard aging mechanisms is considered. My associates and I have previously found that long-term administration of glucocorticoids can increase the development of a brain correlate of aging in rats (astrocyte hypertrophy in hippocampus), and that plasma levels of corticosterone, and adrenal weights, are correlated with astrocyte hypertrophy in spontaneously aging rats. Therefore, the effects of long-term reductions of adrenocorticosteroids would be among the first manipulations examined. Additionally, ACTH, vasopressin analogs, stimulants, L-dopa, insulin, thyroid hormones, blood pressure, and calcium would also be studied in long-term paradigms.